The present invention relates to therapeutically active hydroxamic and carboxylic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine. In particular, the compounds are inhibitors of matrix metalloproteinases involved in tissue degradation.
The matrix metalloproteinases (MMPs) are a family of enzymes including interstitial collagenase, neutrophil collagenase, collagenase-3, 72 kDa gelatinase, 92 kDa gelatinase, stromelysin-1, stromelysin-2, stromelysin-3, matrilysin, macrophage metalloelastase, membrane-type metalloproteinase-1 and membrane-type metalloproteinase-2. These enzymes share a common zinc-containing catalytic domain and a pro-sequence which maintains latency. A wide range of cells and tissues can express MMPs in response to activation by inflammatory stimuli such as interleukin-1 or tumour necrosis factor-xcex1 (TNF-xcex1). Different stimuli can induce overlapping yet distinct repertoires of MMPs and different cell types can respond to the same stimuli by expression of distinct combinations of MMPs. MMPs can attack the protein components of extracellular matrix such as collagens, vitronectin and elastin, and have recently been shown to process membrane proteins such as pro-TNF-xcex1 to release soluble TNF-xcex1. MMPs are thought to play a central role in the pathology of inflammatory diseases such as rheumatoid arthritis as well as in the growth and metastasis of tumours.
Compounds which have the property of inhibiting the action of MMPs are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group or a carboxylic group respectively as their zinc binding groups. Many such known MMPs may be represented by the structural formula (IA) 
in which X is the zinc binding hydroxamic acid (xe2x80x94CONHOH) or carboxylic acid (xe2x80x94COOH) group and the groups R1 to R5 are variable in accordance with the specific prior art disclosures of such compounds.
The following patent publications disclose such MMP inhibitors:
M. A. Abreo et al. presented a poster entitled xe2x80x9cTruncated Succinamide Hydroxamates With Nanomolar Potency against various MMPSxe2x80x9d at the 213th ACS Meeting in San Francisco, Apr. 13th-17th 1997. In that poster compounds of formula (IC) were disclosed: 
wherein X is xe2x80x94COOH or xe2x80x94CONHOH, P1 is biphenylpropyl, R is hydroxymethyl and P2 is the side chain found in one of the following amino acids, namely serine, tert-butylglycine, histidine, O-benzylthreonine, phenylalanine, tyrosine, methionine, threonine, and 3-(3-pyridyl)alanine. Also disclosed were compounds of formula (IC) wherein X and P1 are as just defined, and P2 and R together with the carbon atom to which they are attached form a trans-cyclohexan-2-ol or glucosyl ring. The authors stated that the compound (IC), P2=the histidine side chain and R=hydroxymethyl, showed good plasma levels after iv and oral dosing to mice. They also stated that the X-ray crystal structure of compound (IC), P2=tert-butyl and R=hydroxymethyl, was obtained with stromelysin-1, and that the hydroxyl moiety in R makes an H-bond in the P3 area of the enzyme, while the tert-butyl group makes good hydrophobic contact in the P2 area.
This invention makes available a novel class of compounds which are inhibitors of matrix metalloproteinases. The compounds of the invention conform to general formula (IA), or have structural features similar to those of Abreo et. al., but differ in structure from prior art compounds of formula (IA) or (IC) principally in the identity of the group R1. In the compounds of the present invention, the group R1 is a sulfonamidoalkyl group.
According to the present invention there is provided a compound of formula (I) 
wherein
X is xe2x80x94COOH or xe2x80x94CONHOH
n is 1, 2, 3 or 4;
R2 is a
C1-C12 alkyl,
C2-C12 alkenyl,
C2-C12 alkynyl,
phenyl(C1-C6 alkyl)-,
heteroaryl(C1-C6 alkyl)-,
non-aryl heterocyclyl(C1-C6 alkyl)-,
cycloalkyl(C1-C6 alkyl)-,
cycloalkenyl(C1-C6 alkyl)-,
phenoxy(C1-C6 alkyl)-,
heteroaryloxy(C1-C6 alkyl)-,
phenyl(C1-C6 alkyl)O(C1-C6 alkyl)-,
heteroaryl(C1-C6 alkyl)O(C1-C6 alkyl)-,
phenyl(C1-C6 alkyl)S(C1-C6 alkyl)- or
heteroaryl(C1-C6 alkyl)S(C1-C6 alkyl)- group, any one of which may be optionally substituted by C1-C6 alkyl, trifluoromethyl, C1-C6 alkoxy, halo, cyano (xe2x80x94CN), phenyl, substituted phenyl or heteroaryl; or
R3 represents the characterising group of a natural or non-natural a amino acid in which any functional groups may be protected;
R8 is hydrogen, C1-C6 alkyl, benzyl, acyl, optionally substituted phenyl, optionally substituted heterocyclyl, an amino protecting group, or a group xe2x80x94(CH2)mCOZ where m is an integer from 1 to 6, and Z represents OH, C1-C6 alkoxy or xe2x80x94NRxRy where Rx, Ry each independently represent hydrogen or C1-C6 alkyl; and
R9 is optionally substituted C1-C6 alkyl, cycloalkyl, cycloalkenyl, di-(C1-C6 alkyl)amino, heterocyclyl, phenyl, naphthyl, or heteroaryl; or
R8 and R9 taken together represent a divalent C3-C6 alkylene or alkenylene group which may optionally be (i) substituted by an oxo group, and/or (ii) substituted by (C1-C6)alkoxy, hydroxy, mercapto, (C1-C6)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), cyano, trifluoromethyl, nitro, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94CONHRA or xe2x80x94CONRARA wherein RA is a (C1-C6)alkyl group, and/or (iii) fused to a phenyl or heteroaryl group which itself may be substituted;
Y Is a group of formula (ID) or (IE) 
xe2x80x83wherein:
R4 represents
(a) an optionally substituted cycloalkyl or cycloalkenyl ring; or
(b) a phenyl or heteroaryl ring which may be fused to a benzene or heteroaryl ring, either or both of which rings may be substituted, and in which any ring nitrogen atom may be oxidised as an N-oxide, or
(c) a group xe2x80x94CHRxRy wherein Rx and Ry each independently represents an optionally substituted phenyl or heteroaryl ring which may be linked covalently to each other by a bond or by a C1-C4 alkylene or C2-C4 alkenylene bridge;
(d) a group of formula xe2x80x94(Zxe2x80x2xe2x80x94O)wxe2x80x94Z wherein Zxe2x80x2 is straight or branched C1-C8 alkyl optionally interrupted by one or more non-adjacent S and/or N atoms, w is an integer  greater than 1, and no continuous linear sequence of atoms in the group R4 is  greater than 12, or
(e) a straight or branched C1-C6 alkyl group, optionally interrupted by one or more non-adjacent S and/or N atoms, which is substituted by at least two substituents of formula xe2x80x94(Zxe2x80x2xe2x80x3)xxe2x80x94(OZ)q wherein Zxe2x80x2xe2x80x3 is straight or branched C1-C6 alkyl optionally interrupted by one or more non-adjacent S and/or N atoms, x is 0 or 1, q is 1 or 2, and no continuous linear sequence of atoms in the group R4 is  greater than 12, or
(f) hydrogen, C1-C6 alkyl, C1-C4 perfluoroalkyl, or a group D-(C1-C6 alkyl)- wherein D is hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, acylamino, optionally substituted phenyl or heteroaryl, NH2, or mono- or di-(C1-C6 alkyl)amino or N-morpholino;
or R3 and R4 taken together represent a divalent chain of formula xe2x80x94C(Ra)(Rb)xe2x80x94Axe2x80x3xe2x80x94Alkxe2x80x94 wherein Ra and Rb are independently hydrogen or C1-C6 alkyl, Axe2x80x3 is a bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NRaxe2x80x94 wherein Ra is C1-C6 alkyl, and Alk is C1-C6 alkylene;
R5 is hydrogen or a C1-C6 alkyl group;
R6 is hydrogen, C1-C6 alkyl, phenyl(C1-C6 alkyl), heterocyclyl(C1-C6 alkyl), optionally substituted phenyl, or optionally substituted heterocyclyl;
R7 is is hydrogen or a C1-C6 alkyl group;
or (when R7 is hydrogen) R3 and R7 taken together with the carbon atoms to which they are attached form a 2-hydroxycyclohexyl or C6 sugar (hexose) ring;
or R6 and R7 taken together with the carbon atom to which they are attached form a 5 or 6-membered carbocyclic or heterocyclic ring;
and pharmaceutically acceptable salts, hydrates and solvates thereof.
As used herein the term xe2x80x9calkylxe2x80x9d means a straight or branched chain alkyl moiety. The term xe2x80x9c(Cx-Cy)alkylxe2x80x9d where x and y are integers means an alkyl group having having from x to y carbon atoms. The term xe2x80x9clower alkylxe2x80x9d means an alkyl group having having from 1 to 6 carbon atoms.
The term xe2x80x9calkenylxe2x80x9d means a straight or branched chain alkenyl moiety having at least one double bond of either E or Z stereochemistry where applicable. The term xe2x80x9c(Cx-Cy)alkenylxe2x80x9d where x and y are integers means an alkenyi group having having from x to y carbon atoms. The term xe2x80x9clower alkenylxe2x80x9d means an alkenyl group having from 1 to 6 carbon atoms.
The term xe2x80x9calkynylxe2x80x9d means a straight or branched chain alkynyl moiety having at least one triple bond. The term xe2x80x9c(Cx-Cy)alkynylxe2x80x9d where x and y are integers means an alkynyl group having having from x to y carbon atoms. The term xe2x80x9clower alkynylxe2x80x9d means an alkynyl group having having from 1 to 6 carbon atoms.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated alicyclic ring having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein means an unsaturated alicyclic ring having from 5-8 carbon atoms, incorporating at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
The term xe2x80x9cacylxe2x80x9d as used herein means a group RC(xe2x95x90O)xe2x80x94 wherein R is C1-C6 alkyl or substituted C1-C6 alkyl, phenyl or substituted phenyl, phenyl(C1-C6 alkyl)- or subtituted phenyl(C1-C6 alkyl)-.
The term xe2x80x9cnon-aryl heterocyclylxe2x80x9d means a 5-7 membered heterocyclic ring containing one, two or three heteroatoms selected from S, N and O in which at least two adjoining atoms are saturated. Examples include morpholinyl, thiomorpholinyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, piperidinyl, pyrrolidinyl, pyrrolinyl, dioxolanyl, oxathiolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, pyranyl, dioxanyl, dithianyl, oxathianyl, and piperazinyl.
The term xe2x80x9cheteroarylxe2x80x9d means a 5-7 membered aromatic heterocyclic ring containing one or more heteroatoms selected from S, N and O and optionally fused to a benzene ring. Illustrative of such rings are thienyl, furyl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
Unless otherwise specified in the context in which it occurs, the term xe2x80x9csubstitutedxe2x80x9d as applied to any moiety herein means substituted with up to four substituents, each of which independently may be (C1-C6)alkoxy, hydroxy, mercapto, (C1-C6)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), cyano, trifluoromethyl, nitro, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94CONHRA or xe2x80x94CONRARA wherein RA is a (C1-C6)alkyl group or the residue of a natural alpha-amino acid, or substituted with a phenyl or heteroaryl group which itself may be substituted by any of the foregoing.
The term xe2x80x9cside chain of a natural or non-natural alpha-amino acidxe2x80x9d means the group R in a natural or non-natural amino acid of formula NH2xe2x80x94CH(R)xe2x80x94COOH.
Examples of side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, a-aminoadipic acid, a-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, a-methylserine, ornithine, pipecolic acid, and thyroxine.
Natural alpha-amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups in their characteristic side chains include arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine, and cysteine. When R3 in the compounds of the invention is one of those side chains, the functional substituent may optionally be protected.
The term xe2x80x9cprotectedxe2x80x9d when used in relation to a functional substituent in a side chain of a natural alpha-amino acid means a derivative of such a substituent which is substantially non-functional. For example, carboxyl groups may be esterified (for example as a C1-C6 alkyl ester), amino groups may be converted to amides (for example as a NHCOC1xe2x80x94C6 alkyl amide) or carbamates (for example as an NHC(xe2x95x90O)OC1xe2x80x94C6 alkyl or NHC(xe2x95x90O)OCH2Ph carbamate), hydroxyl groups may be converted to ethers (for example an OC1xe2x80x94C6 alkyl or a O(C1-C6 alkyl)phenyl ether) or esters (for example a OC(xe2x95x90O)C1-C6 alkyl ester) and thiol groups may be converted to thioethers (for example a tert-butyl or benzyl thioether) or thioesters (for example a SC(xe2x95x90O)C1-C6 alkyl thioester).
Examples of side chains of non-natural alpha amino acids include those referred to below in the discussion of suitable R3 groups for use in compounds of the present invention.
Salts of the compounds of the invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulfates, methane sulfonates, p-toluenesulfonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. Salts may also be formed with bases, for example sodium, potassium, magnesium, and calcium salts.
There are at least two chiral centres in the compounds according to the invention because of the presence of asymmetric carbon atoms. The presence of these asymmetric carbon atoms gives rise to a number of diastereomers with R or S stereochemistry at each chiral centre. General formula (1), and (unless specified otherwise) all other formulae in this specification are to be understood to include all such stereoisomers and mixtures (for example racemic mixtures) thereof.
In the compounds of the invention, the preferred stereochemistry is in general as follows:
C atom carrying the X groupxe2x80x94S,
C atom carrying the R2 groupxe2x80x94R,
C atom carrying the R3 groupxe2x80x94S, but mixtures in which the above configurations predominate are also contemplated.
As mentioned above, the compounds of the present invention differ in structure from the collagenase inhibitors disclosed in the patent publications listed above principally in that they have the above defined R9xe2x80x94(SO2)xe2x80x94N(R8)xe2x80x94(CH2)nxe2x80x94 group on the carbon atom carrying the hydroxamic acid group. Accordingly the groups R2, R3, R4, R5, R6 and R7 of the compounds of this invention may include those which have been disclosed in the corresponding positions of compounds disclosed in any of the patent publications listed above.
Without limiting the generality of the foregoing, examples of substituents R2 to R9 are given below:
The Group R2 
In the compounds of the invention, two classes of substituent R2 are those having formula (A) or (B): 
wherein
In this type of R2 group:
(i) heteroaryl Ar groups may be bonded via a ring carbon atom in Ar or (in the case where t is 0) via a ring nitrogen atom in Ar;
(ii) when the group Ar is substituted, preferably only one substituent is present. In 6 membered Ar groups, such as phenyl and pyridyl, the substituent is preferably in the 4-position of the ring relative to the bond connecting Ar to the rest of group (II). In 5 membered Ar groups, such as thienyl and furanyl, the substituent is preferably in the 3- or 4-position of the ring relative to the bond connecting Ar to the rest of group (Il);
(iii) a sole substituent in Ar may be selected from C1-C6 alkyl eg methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl; C1-C6 alkoxy(C1-C6 alkoxy), 2-methoxyethoxy, trifluoromethyl, halo eg chloro, cyano (xe2x80x94CN), xe2x80x94CH2CN, xe2x80x94OH, or xe2x80x94OR, wherein R is C1-C6 alkyl or benzyl;
(iv) another sole substituent in Ar may be a phenyl, phenoxy, phenylthio, heteroaryl (eg 2-, 3- or 4-pyridyl), heteroaryloxy (eg 2-, 3- or 4pyridyloxy) or heteroarylthio ((eg 2-, 3- or 4-pyridylthio) group which is either unsubstitued or substituted with one substituent selected from C1-C6 alkyl eg methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl; C1-C6 alkoxy(C1-C6 alkoxy), 2-methoxyethoxy, trifluoromethyl, halo eg chloro, cyano (xe2x80x94CN), xe2x80x94CH2CN, xe2x80x94OH, and xe2x80x94OR, wherein R is C1-C6 alkyl or benzyl;
(v) r may be 1 or 2 and s may be 1.
The R2 group present in the compounds of the invention may be:
optionally substituted C1-C12 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, or cycloalkyl(C1-C6 alkyl); or
phenyl(C1-C6 alkyl)- or phenoxy(C1-C6 alkyl)-, either of which may be optionally substituted in the phenyl ring by halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy; or
biphenyl(C1-C6 alkyl)-, 4xe2x80x2-phenoxy(phenyl(C1-C6 alkyl))-, 4xe2x80x2-pyrid-2,3 or 4-yl(phenyl(C1-C6 alkyl))-, or 4xe2x80x2-pyrid-2,3 or 4-yloxy(phenyl(C1-C6 alkyl))-, any of which may optionally be substituted in the terminal phenyl or pyridyl ring by halogen, cyano, C1-C6 alkyl, or C1-C6 alkoxy.
Specific examples of R2 groups present in the compounds of the invention include isopropyl, iso-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1,1,1-trifluoropropyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 4-phenyl-phenylpropyl, 4-(4-chlorophenyl)phenylpropyl, 4-phenoxyphenylethyl, 4-(4-chlorophenoxy)phenylethyl, 4-pyrid-4-ylphenylpropyl, 4-pyrid-4-yloxyphenylethyl, 4-(4-chlorophenoxy)phenylethyl, 4-chlorophenylprop-2-ynyl, 4-biphenyl-4-ylprop-2-ynyl, and phenoxybutyl.
The Group R3 
In the compounds of the invention, R3 may for example be C1-C6 alkyl, benzyl, 2,-3-, or 4-hydroxybenzyl, 2,-3-, or 4-benzyloxybenzyl, 2,-3-, or 4-C1-C6 alkoxybenzyl, or benzyloxy(C1-C6alkyl)- group; or
the characterising group of a natural a amino acid, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; or
a group a group xe2x80x94[Alk]nR10 where Alk is a (C1-C6)alkyl or (C2-C6)alkenyl group optionally interrupted by one or more xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94 groups [where R11 is a hydrogen atom or a (C1-C6)alkyl group], n is 0 or 1, and R10 is an optionally substituted cycloalkyl or cycloalkenyl group; or a benzyl group substituted in the phenyl ring by a group of formula xe2x80x94OCH2COR12 where R12 is hydroxyl, amino, (C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkylamino, di((C1-C6)alkyl)amino, phenyl(C1-C6)alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, a or b alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid.; or
a heterocyclic(C1-C6)alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C1-C6)alkoxy, cyano, (C1-C6)alkanoyl, trifluoromethyl (C1-C6)alkyl, hydroxy, formyl, amino, (C1-C6)alkylamino, di-(C1-C6)alkylamino, mercapto, (C1-C6)alkylthio, hydroxy(C1-C6)alkyl, mercapto(C1-C6)alkyl or (C1-C6)alkylphenylmethyl; or
a group xe2x80x94CRaRbRc in which:
each of Ra, Rb and Rc is independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, (C3-C8)cycloalkyl; or
Rc is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, or (C3-C8)cycloalkyl, and Ra and Rb together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or
Ra, Rb and Rc together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or
Ra and Rb are each independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl(C1-C6)alkyl, or a group as defined for Rc below other than hydrogen, or Ra and Rb together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and Rc is hydrogen, xe2x80x94OH, xe2x80x94SH, halogen, xe2x80x94CN, xe2x80x94CO2H, (C1-C4)perfluoroalkyl, xe2x80x94CH2OH, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94O(C1-C6)alkyl, xe2x80x94O(C2-C6)alkenyl, xe2x80x94S(C1-C6)alkyl, xe2x80x94SO(C1-C6)alkyl, xe2x80x94SO2(C1-C6) alkyl, xe2x80x94S(C2-C6)alkenyl, xe2x80x94SO(C2-C6)alkenyl, xe2x80x94SO2(C2-C6)alkenyl or a group xe2x80x94Qxe2x80x94W wherein Q represents a bond or xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94or xe2x80x94SO2xe2x80x94 and W represents a phenyl, phenylalkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkylalkyl, (C4-C8)cycloalkenyl, (C4-C8)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94CONH2, xe2x80x94CONH(C1-C6)alkyl, xe2x80x94CONH(C1-C6alkyl)2, xe2x80x94CHO, xe2x80x94CH2OH, (C1C4)perfluoroalkyl, xe2x80x94O(C1-C6)alkyl, xe2x80x94S(C1-C6)alkyl, xe2x80x94SO(C1-C6)alkyl, xe2x80x94SO2(C1-C6)alkyl, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NH(C1-C6)alkyl, xe2x80x94N((C1-C6)alkyl)2, xe2x80x94NHCO(C1-C6)alkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl, phenyl or benzyl.
Examples of particular R3 groups include benzyl, iso-butyl, tert-butyl, 1-fluoro-1-methylethyl, 1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl and 1-mercapto-1-methylethyl. Presently preferred are compounds in which R3 is benzyl, t-butyl, 1-mercapto-1-methylethyl or 3H-imidazol-4-yl-methyl.
The Groups R4 and R5 
In compounds of the invention wherein Y is a group (ID), R4 may for example be
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cycloheptyl or cyclooctyl;
optionally substituted phenyl, napthyl, furanyl, thienyl, pyrrolinyl, tetrahydrofuranyl, imidazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridinyl N-oxides, piperazinyl, indolyl, benzimidazolyl, benzotriazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, dithianyl, benzo[b]thienyl, isoxazolyl or quinolinyl. Examples of particular R4 groups of this type include phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethyl, 2-t-butylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 4-t-butyl-2,6-dimethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 2-methylsulphonylphenyl, 3-methylsulphonylphenyl, 4-methylsulphonylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-ditrifluoro-methylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-N,N-dimethyl-aminophenyl, 3-N,N-dimethylaminophenyl, 4-N,N-dimethylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-napthyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, tetrahydrofuran-2-yl, imidazol-2-yl, thiazol-2-yl, 4-ethoxycarbonyl-methylthiazol-2-yl, 4-phenylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 5-bromothiazol-2-yl, 4-tert-butylthiazol-2-yl, benzothiazol-2-yl, 1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxides of pyridin-2-yl pyridin-3-yl and pyridin4-yl, piperazin-1-yl, indol-2-yl, benzimidazol-2-yl, benzotriazol-2-yl, pyrazin-2-yl, 1,2-pyridazin-3-yl, 1,3-pyrimidin-5-yl, 1,3-dithian-2-yl, benzo[b]thien-2-yl, isoxazol-5-yl, quinolin-3-yl. Presently preferred are compounds in which R4 is phenyl, 3-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, and thiazol-2-yl, 4,5-dimethylthiazol-2-yl, 5-bromothiazol-2-yl, 4-ethoxycarbonylmethylthiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl or 4-tertbutylthiazol-2-yl. Particularly preferred R4 groups of this type are 3-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, 4-ethoxycarbonylmethylthiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl or 4-tert-butylthiazol-2-yl;
a group xe2x80x94CHRxRy wherein Rx and Ry independently represent optionally substituted phenyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinolyl, pyrimidinyl, piperazinyl or triazinyl. Examples of particular Rx and Ry include phenyl, 4-chlorophenyl and pyridinyl. Where Rx and Ry are linked covalently, an example of a group R4 is 9-H-fluoren-9-yl;
a polyether chain possessing at least two non-adjacent oxygen atoms, for example 2-(2-methoxyethoxymethoxy)ethyl, 1,1-dimethyl-2-(2-methoxyethoxymethoxy)ethyl, 2-(2-ethoxyethoxymethoxy)ethyl, 2-(2-(2-methoxyethoxy)ethoxy)ethyl, 2-(2-(3-methoxypropoxymethoxy)ethyl, 3-(2-methoxyethoxymethoxy)propyl, 2,2-dimethyl-3-(2-methoxyethoxymethoxy)propyl, 2-(2-methoxyethoxy)ethyl, 3-(2-methoxyethoxy)-propyl, 2-methyl-2,2-di(2-methoxyethyl)propyl, 2-methyl-2,2-di(2-methoxyethyl)butyl, and 2-methyl-2,2-di(2-methoxymethyl)propyl. A presently preferred R4 group of this type is 2-(2-methoxyethoxy)ethyl;
methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, hydroxyethyl, hydroxypropyl, 2,2-dimethyl-3-hydroxypropyl, hydroxybutyl, methoxyethyl, ethoxyethyl, methoxypropyl, 2,2-dimethyl-3-methoxypropyl, 2,2-dimethyl-3-ethoxypropyl, 2-ethylthioethyl, 2-acetoxyethyl, N-acetyl-aminoethyl, 3-(2-pyrrolidone)propyl, morpholin-4-ylpropyl, optionally substituted phenylethyl, phenylpropyl, phenylbutyl, or phenylpentyl. Presently preferred R4 groups of this type are hydrogen, methyl or morpholin-4-ylpropyl.
In compounds of the invention wherein Y is a group (ID), where R3 and R4 taken together represent a divalent chain of formula xe2x80x94C(Ra)(Rb)xe2x80x94Axe2x80x94Alkxe2x80x94 wherein Ra and Rb are independently hydrogen or C1-C6 alkyl, A is a bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NRaxe2x80x94 wherein Ra is C1-C6 alkyl, and Alk is C1-C6 alkylene, examples of such divalent chains include xe2x80x94C(CH3)2SCH2CH2CH2xe2x80x94, and xe2x80x94C(CH3)2SSCH2CH2xe2x80x94.
In compounds of the invention wherein Y is a group (ID), examples of particular R5 groups include hydrogen, methyl and ethyl. Presently preferred are compounds in which R5 is methyl.
In one particular class of compounds of the invention wherein Y is a group (ID), R4 and R5 are both methyl.
The Groups R6 and R7 
In compounds of the invention wherein Y is a group (IE), R6 may be, for example, hydrogen, methyl, ethyl, benzyl or pyridylmethyl, and R7 may be, for example hydrogen or methyl. R6 and R7 taken together with the carbon atom to which they are attached may form, for example, a cyclopentyl, cyclohexyl or morpholino ring. Presently preferred are compounds in which R6 and R7 are both hydrogen.
In compounds of the invention wherein Y is a group (IE), when R7 is hydrogen, R3 and R6 taken together with the carbon atoms to which they are attached may form a 2-hydroxycyclohexyl or a glucose ring.
The Group R8 
R8 may for example be hydrogen, methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, n-pentyl, n-hexyl, benzyl, or acetyl. Presently preferred are compounds in which R8 is hydrogen, acetyl or methyl.
The Group R9 
R9 may for example be substituted or unsubstituted methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, di-(C1-C6 alkyl)amino such as dimethyl- or diethyl-amino, phenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl. Specific examples of substituted R9 groups include benzyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethyl, 2-t-butylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 4-t-butyl-2,6dimethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-N,N-dimethylaminophenyl, 3-N,N-dimethylaminophenyl, 4-N,N-dimethylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, naphth-1-yl and naphth-2-yl; furan-2-yl, thien-2-yl, imidazol-2-yl, thiazol-2-yl, 4-ethoxycarbonylmethyl-thiazol-2-yl, 4-phenylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 5-bromothiazol-2-yl, 4-tert-butylthiazol-2-yl, benzothiazol-2-yl, 1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 1,2.4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxides of pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, piperazin-1-yl, indol-2-yl, benzimidazol-2-yl, benzotriazol-2-yl, pyrazin-2-yl, 1,2-pyridazin-3-yl, 1,3-pyrimidin-5-yl, 1,3-dithian-2-yl, benzo[b]thien-2-yl, isoxazol-5-yl, and quinolin-3-yl. Presently preferred are compounds in which R9 is methyl, dimethylamino, trifluoromethyl, phenyl, 4-methoxyphenyl, 4-chlorophenyl, naphth-1-yl, naphth-2-yl or thien-2-yl.
R8 and R9 taken together with the N and S atoms to which they are attached may represent a group of formula (XI) or (XII) 
wherein ring A is a substituted or unsubstituted, saturated or unsaturated 5-8 membered ring and ring B is a substituted or unsubstituted fused phenyl orheteroaryl (e.g. thienyl or pyridinyl) ring.
Specific compounds of the invention include:
N4-(1S-dimethylaminocarbamoyl-2,2-dimethyl-propyl)-N1-hydroxy-3R-isobutyl-2R-[(methanesulfonyl-methyl-amino)-methyl]-succinamide,
N1-hydroxy-3R-isobutyl-2R-[(methanesulfonyl-methyl-amino)-methyl]-N4-{1S-[2-(2-methoxy-ethoxy)-ethyl-carbamoyl]-2,2-dimethyl-propyl}-succinamide,
N4-(1S-benzyl-2-hydroxy-ethyl)-N1-hydroxy-3R-isobutyl-2R-[(methanesulfonyl-methyl-amino)methyl]-succinamide,
N1-hydroxy-N4-(1S-hydroxymethyl-2,2-dimethylpropyl)-3R-isobutyl-2R-[(methanesulfonyl-methyl-amino)-methyl]-succinamide,
N1-hydroxy-N4-[2-hydroxy-1S-(1H-imidazol-4-ylmethyl)ethyl]-3R-isobutyl-2S-[(methanesulfonyl-methyl-amino)-methyl]-succinamide.
N1-hydroxy-N4-[2-hydroxy-1S-(4-hydroxy-benzyl)-ethyl]-3R-isobutyl-2S-[(methanesulfonyl-methyl-amino)methyl]-succinamide,
N4-(1S-dimethylcarbamoyl-2,2-dimethyl-propyl)-N1-hydroxy-3R-isobutyl-2S-{[(4-methoxy-benzenesulfonyl)-methyl-amino]-methyl}-succinamide,
N4-(1S-benzyl-2-hydroxy-ethyl)-N 1-hydroxy-3R-isobutyl-2S-{[(4-methoxy-benzenesulfonyl)-methyl-amino]-methyl}succinamide,
3R-(3-biphenyl4-yl-propyl)-N1-hydroxy-N4-[2S-hydroxy-1-(1H-imidazol-4-ylmethyl)-ethyl]-2S-{[(4-methoxy-benzenesulfonyl)-methyl-amino]-methyl}-succinamide,
3R-cyclopentylmethyl-N1-hydroxy-N4-(1S-hydroxymethyl-2,2-dimethyl-propyl)-2S-{[(4-methoxy-benzenesulfonyl)-methyl-amino]-methyl}-succinamide,
3R-cyclopentylmethyl-2S-{[(5-dimethylamino-naphthalene-1-sulfonyl)methyl-amino]-methyl}-N1-hydroxy-N4-(1S-hydroxymethyl-2,2-dimethyl-propyl)-succinamide,
N1-(1S-benzyl-2-hydroxy-ethyl)-3R-(3-biphenyl-4-yl-propyl)-N1-hydroxy-2S-[(methanesulfonyl-methyl-amino)-methyl]-succinamide,
3R-(3-biphenyl-4-yl-propyl)-N1-hydroxy-N4-(1S-hydroxymethyl-2,2dimethyl-propyl)-2S-{[(4-methoxy-benzenesulfonyl)-methyl-amino]-methyl}succinamide,
N4-(1S-benzyl-2-hydroxy-ethyl)-3R-(3-biphenyl-4-yl-propyl)-N1-hydroxy-2S-{[(4-methoxy-benzenesulfonyl)-methyl-amino]-methyl}-succinamide
and pharmaceutically acceptable salts, hydrates and solvates thereof.
Compounds of the invention wherein X is HONHxe2x80x94 may be prepared by a process which comprises causing an acid of the invention of general formula (II) 
or an activated derivative thereof to react with hydroxylamine, O-protected hydroxylamine, N,O-diprotected hydroxylamine, or a salt thereof, n, Y, R2, R3, R8, and R9, being as defined in general formula (I) except that any substituents in Y, R2, R3, R8, and R9 which are potentially reactive with hydroxylamine, the O-protected hydroxylamine, the N,O-iprotected hydroxylamine or their salts may themselves be protected from such reaction, then removing any protecting groups from the resultant hydroxamic acid moiety and from any protected substituents in Y, R2, R3, R8, and R9.
Conversion of (II) to an activated derivative such as the pentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl ester may be effected by reaction with the appropriate alcohol in the presence of a dehydrating agent such as dicyclohexyl dicarbodiimide (DCC), N,N-dimethylaminopropyl-Nxe2x80x2-ethyl carbodiimide (EDC), or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ).
Protecting groups as referred to above are well known per se, for example from the techniques of peptide chemistry. Amino groups are often protectable by benzyloxycarbonyl, t-butoxycarbonyl or acetyl groups, or in the form of a phthalimido group. Hydroxy groups are often protectable as readily cleavable ethers such as the t-butyl or benzyl ether, or as readily cleavable esters such as the acetate. Carboxy groups are often protectable as readily cleavable esters, such as the t-butyl or benzyl ester.
Examples of O-protected hydroxylamines for use in the process of the invention above include O-benzylhydroxylamine, O-4-methoxybenzylhydroxylamine, O-trimethylsilylhydroxylamine, and O-tert-butoxycarbonylhydroxylamine.
Examples of O,N-diprotected hydroxylamines for use in the process of the invention include N,O-bis(benzyl)hydroxylamine, N,O-bis(4-methoxybenzyl)hydroxylamine, N-tert-butoxycarbonyl-O-tert-butyldimethylsilylhydroxylamine, N-tert-butoxycarbonyl-O-tetrahydropyranylhydroxylamine, and N,O-bis(tert-butoxycarbonyl)hydroxylamine.
Acids of the invention (II) may be prepared by forming the appropriate R9-sulfonamide of an amine of formula (III), for example by reaction with an activated derivative of a sulphonic acid (IV), 
wherein P1 is a protected carboxyl group and n, Y, R2, R3 and R8 are as defined in relation to formula (I) except that any substituents in Y, R2, R3 and R8 which are potentially reactive with (IV) may be protected, and thereafter deprotecting the protected carboxyl group P1 and any protected substituents in Y, R2, R3, and R8. Activated sulphonic acids and conditions for forming sulfonamides are well known in organic synthesis, e.g. reaction with the sulfonyl chloride in the presence of an organic base.
Amines of formula (III) in which R8 is hydrogen may be prepared from the corresponding hydroxyl compound of formula (IIIA) 
by methods known in organic synthesis for conversion of hydroxyl groups to amine groups, e.g. by conversion the hydroxyl group of (IIIA) to a leaving group, displacement with azide, followed by catalytic hydrogenation of the azide group.
Amines of formula (III) in which R8 is other than hydrogen may be accessible by direct introduction of R8 onto the amine group of the compound (III) wherein R8 is hydrogen. In the special case of compounds (III) wherein n is 1, ammination of the double bond of compounds (V) 
with the amine R8NH2 can provide a convenient route.
Compounds (IIIA) and (V) may be prepared by reaction of an amine (VI) 
wherein Y and R3 are as defined in relation to formula (IIIA), with the corresponding carboxylic acids (VII) or (VIII) 
wherein n, P1 and R2 are as defined in relation to formula (IIIA) and P2 is a protected hydroxyl group, which is converted to the required hydroxyl group after the reaction with amine (VI).
Amino acid amides and amino alcohols of formula (VI, and ) compounds (VII) and (VIII) are either known, are analogues of known compounds, or are accessible by known literature methods. For example, compounds of formula (VII) and (VIII) wherein R2 is a triple unsaturated radical of formula (B) above may in many cases be prepared by alkylation of a the corresponding carboxyl protected compound (R2=hydrogen) with a halide of formula (IX)
Hxe2x80x94(Cxe2x89xa1C)rxe2x80x94(CH2)sxe2x80x94Lxe2x80x83xe2x80x83(IX)
wherein r and s are as defined in relation to formula (B) and L is a reactive halo group (eg bromo) capable of reacting with (VII) or (VIII) at the C atom adjacent the protected carboxyl group with elimination of the elements of HL and then reacting the resultant compound with a halide Arxe2x80x94L, wherein Ar is as defined in relation to formula (B) and L is again a reactive halo group, under palladium catalysis (the Heck reaction; see R. F. Heck, Palladium Reagents in Organic Synthesis, Academic Press, London 1985), again with elimination of the elements of HL. The terminal hydrogen of compound (IX) may optionally be protected during the reaction, for example as a silyl derivative such as trimethylsilyl.
As mentioned above, compounds of formula (I) are useful in human or veterinary medicine since they are active as inhibitors of MMPs.
Accordingly in another aspect, this invention concerns:
(i) a method of management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound as defined with respect to formula (I) above, or a pharmaceutically acceptable salt thereof; and
(ii) a compound as defined with respect to formula (I) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs; and
(iii) the use of a compound as defined with respect to formula (I) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by MMPs.
Diseases or conditions mediated by MMPs include those involving tissue breakdown such as bone resorption, inflammatory diseases, dermatological conditions and tumour invasion by secondary metastases, in particular rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration and tumour invasion by secondary metastases as well as neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis.
In a further aspect of the invention there is provided a pharmaceutical or veterinary composition comprising a compound of formula (I) together with a pharmaceutically or veterinarily acceptable excipient or carrier.
One or more compounds of general formula (I) may be present in the composition together with one or more excipient or carrier.
The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
The dosage unit involved in oral administration may contain from about 1 to 250 mg, preferably from about 5 to 100 mg of a compound of the invention. A suitable daily dose for a mammal may vary widely depending on the condition of the patient. However, a dose of a compound of general formula I of about 0.1 to 10 mg/kg body weight, particularly from about 0.1 to 3 mg/kg body weight may be appropriate.
For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
For topical application to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite os disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
The dosage for topical administration will of course depend on the size of the area being treated. For the eyes, each dose may typically be in the range from 10 to 100 mg of the drug.
The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
For use in the treatment of rheumatoid arthritis, the drug can be administered by the oral route or by injection intra-articulaey into the affected joint.
The following Examples illustrate embodiments of the invention.
2-Benzyloxycarbonyl-3R-carboxy-5-methyl-hexanoic acid 1-benzyl ester 4-tert-butyl ester was prepared as described in EP 0 446 267. L-tert-leucine-N-2-(2-methoxy-ethoxy) ethylamide was prepared as described in WO 96/16931. L-tert-leucine-N,N-dimethylamide was prepared by a similar method. 3R-cyclopentylmethyl-succinic acid 1-benzyl ester 4-tert-butyl ester was prepared by Evans"" methodology, as described in WO 92/13831. The following abbreviations have been used throughout:
1H and 13C NMR spectra were recorded using a Bruker AC 250E spectrometer at 250.1 and 62.9 MHz, respectively. Infra red spectra were recorded using a Perkin Elmer 1600 Series FTIR spectrometer. Elemental microanalyses were performed by Medac Ltd. (Department of Chemistry, Brunel University, Uxbridge, Middlesex UB8 3PH).